The present invention relates to a local anesthetic for external use. In particular, the present invention relates to a local anesthetic for external use, which is conveniently usable and applicable to a broad skin surface, and which is excellent in percutaneous absorption and quick efficacy as well as excellent in stability.
The percutaneous absorption type local anesthetic for external use has advantages in that, for example, it does not require any special technique upon administration, it does not cause any pain, and it makes it possible to anesthetize a broad skin surface, as compared with other types of anesthetics administrated by injections such as cuteneous or subcuteneous injections. Accordingly, the percutaneous absorption type local anesthetic for external use has been considerably investigated (Japanese Laid-Open Patent Publication Nos. 57-81408, 4-305523, and 6-40947). In medical facilities such as hospitals, the local anesthetic for external use is sometimes used in accordance with a method in which an active anesthetic ingredient is blended with, for example, an agent of ointment, cream, or gel to prepare a nosocomial or clinically formulated local anesthetic which is tightly sealed, upon administration, with an extremely air-tight resin film such as a polyvinylidene chloride film (xe2x80x9cODT methodxe2x80x9d; Hifu, 34 (2), 237-242 (1992)). Recently, a tape-shaped medicament has been developed, and it has been commercially available for medical use.
However, the following problems have been pointed out for the conventional pharmaceutical preparations. Namely, any of the pharmaceutical preparations described in the respective patent documents is insufficient in percutaneous absorption and quick efficacy. As for the nosocomial local anesthetic pharmaceutical preparations formulated, for example, as the ointment, the cream, or the gel form agent, some of the pharmaceutical preparations have poor stability, and hence it is necessary for such pharmaceutical preparations to be prepared when they are used. Further, other of the pharmaceutical preparations are inconvenient for use, and they require a long time to express the anesthetic effect. Moreover, the tape-shaped medicament is unsuitable to anesthetize a broad skin surface. Although the anesthetic is blended at a high concentration (30 to 60%), the tape-shaped medicament is deficient in percutaneous absorption and quick efficacy.
The present invention has been made taking the foregoing viewpoints into consideration, an object of which is to provide a percutaneous absorption type local anesthetic for external use which is conveniently used when it is applied and peeled off, which is applicable to a broad skin surface, and which is excellent in percutaneous absorption and quick efficacy as well as excellent in stability.
As a result of diligent investigations performed by the present inventors in order to achieve the object described above, it has been found that when an active ingredient selected from lidocaine, prilocaine, and pharmaceutically acceptable salts thereof is allowed to be contained in a mixed solution comprising water and lower alcohol such as ethanol and isopropyl alcohol, and a resultant solution is allowed to further contain a percutaneous absorption accelerator to formulate a pharmaceutical preparation so that it is used as a percutaneous absorption type local anesthetic, then it is possible to improve the percutaneous absorption of the active ingredient and shorten the time required to express the anesthetic effect, and the pharmaceutical preparation containing the foregoing components is excellent in stability. Thus the present invention has been completed.
Namely, the present invention lies in a local anesthetic for external use, containing a) an active ingredient selected from lidocaine, prilocaine, and pharmaceutically acceptable salts thereof, b) a percutaneous absorption accelerator, c) ethanol and/or isopropyl alcohol, and d) water.
Specifically, the b) percutaneous absorption accelerator contained in the local anesthetic for external use of the present invention preferably includes fatty acids each having a number of carbon atoms of 8 to 18 and pharmaceutically acceptable salts thereof. Among these compounds, those more preferably used include caprylic acid having a number of carbon atoms of 8, oleic acid having a number of carbon atoms of 18, and pharmaceutically acceptable salts thereof.
Specifically, the local anesthetic for external use of the present invention contains c) ethanol and/or isopropyl alcohol and d) water preferably in a ratio of content within a range of 0.5 to 1.2 as expressed by a weight ratio of ethanol and/or isopropyl alcohol to water. The local anesthetic for external use of the present invention preferably has a pH within a range of 6.0 to 8.5.
As for the form of agent, for example, the local anesthetic for external use of the present invention is preferably applied as a gel form agent.
The present invention will be explained in detail below.
The local anesthetic for external use of the present invention contains a) the active ingredient selected from lidocaine, prilocaine, and pharmaceutically acceptable-salts thereof, b) the percutaneous absorption accelerator, c) ethanol and/or isopropyl alcohol, and d) water. The foregoing respective components a) to d) will be successively explained below.
a) Lidocaine, Prilocaine, and Pharmaceutically Acceptable Salts Thereof
Both of lidocaine and prilocaine are compounds known as local anesthetics. These compounds are easily obtained by chemical synthesis. Therefore, chemically synthesized products known as described above can be used for the local anesthetic for external use of the present invention. In general, these compounds are commercially available. Therefore, it is also possible to use commercially available products in the present invention. The local anesthetic for external use of the present invention contains, as the active ingredient, lidocaine or prilocaine singly, or a mixture of them. However, the local anesthetic for external use of the present invention can contain one or more pharmaceutically acceptable salts of lidocaine and prilocaine in place of them or in addition to them. The pharmaceutically acceptable salts specifically include, for example, hydrochloride of lidocaine and hydrochloride of prilocaine.
In the local anesthetic for external use of the present invention, the content of the active ingredient selected from lidocaine, prilocaine, and pharmaceutically acceptable salts thereof is preferably about 2 to 12% by weight, and more preferably 5 to 10% by weight with respect to the total amount of the pharmaceutical preparation, however, the content of the active ingredient varies depending on the type or form of agent, the position at which the agent is used, and the method with which the agent is used.
b) Percutaneous Absorption Accelerator
The percutaneous absorption accelerator contained in the local anesthetic for external use of the present invention is not specifically limited provided that the absorption accelerator has a function to accelerate percutaneous absorption of lidocaine, prilocaine, and pharmaceutically acceptable salts thereof as the active ingredient of the local anesthetic for external use of the present invention, and that the absorption accelerator is a pharmaceutically acceptable compound. Specifically, those preferably used as the percutaneous absorption accelerator include fatty acids each having a number of carbon atoms of 8 to 18 and pharmaceutically acceptable salts thereof. The fatty acid having a number of carbon atoms of 8 to 18 includes, for example, caprylic acid, capric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, and linolenic acid. Among these compounds, those more preferably used for the local anesthetic for external use of the present invention are exemplified by caprylic acid having a number of carbon atoms of 8, and oleic acid having a number of carbon atoms of 18. The pharmaceutically acceptable salts of these fatty acids may include, for example, sodium salts, potassium salts, calcium salts, aluminum salts, and zinc salts.
The content of the percutaneous absorption accelerator of the local anesthetic for external use of the present invention is preferably about 1.0 to 7.0% by weight, and more preferably 2.0 to 4.0% by weight with respect to the total amount of the pharmaceutical preparation, when the fatty acids each having a number of carbon atoms of 8 to 18 or the pharmaceutically acceptable salts thereof are used as the percutaneous absorption accelerator, however, the content of the percutaneous absorption accelerator varies depending on, for example, the type and the content of the active ingredient.
c) Ethanol and/or Isopropyl Alcohol, and d) Water
The local anesthetic for external use of the present invention comprises ethanol and/or isopropyl alcohol and water which are contained as base materials in the local anesthetic for external use. The ratio of ethanol and/or isopropyl alcohol to water, mixed and contained as the base materials in the local anesthetic for external use of the present invention, is preferably within a range of 0.5 to 1.2, and more preferably within a range of 0.6 to a 1.2, as expressed by the weight ratio of ethanol and/or isopropyl alcohol to water.
The total content of ethanol and/or isopropyl alcohol and water, i.e., the content of the base materials in the local anesthetic for external use of the present invention is preferably about 59 to 90% by weight, and more preferably 72 to 80 % by weight with respect to the total amount of the pharmaceutical preparation, however, the total content of ethanol and/or isopropyl alcohol and water varies depending on, for example, the types and the contents of the active ingredient and the percutaneous absorption accelerator.
The local anesthetic for external use of the present invention contains the respective components a) to d) as described above. However, the local anesthetic for external use of the present invention may further contain arbitrary components generally contained in ordinary local anesthetics for external use, if necessary, provided that the arbitrary components are contained within a range in which the effect of the present invention is not deteriorated. Such an arbitrary component is firstly exemplified by a pH-adjusting agent. Considering the viewpoint of the percutaneous absorption, the local anesthetic for external use of the present invention preferably has a pH within a range of about 6.0 to 8.5, and more preferably within a range of 6.0 to 8.0. In order to adjust pH to be within the preferred range described above, the local anesthetic for external use of the present invention may contain one or more agents selected from various pH-adjusting agents including, for example, hydrochloric acid, lactic acid, diisopropanolamine, and triethanolamine. The content of the pH-adjusting agent is preferably not more than 8.0% by weight, and more preferably 0.05 to 5.5% by weight with respect to the total amount of the pharmaceutical preparation.
Besides the pH-adjusting agent described above, the arbitrary component, which may be contained in the local anesthetic for external use of the present invention, may be exemplified by components appropriately contained in conformity with various types or forms of agents to which the local anesthetic for external use of the present invention is applicable. The type or form of agent, to which the local anesthetic for external use of the present invention is applicable, includes, for example, agents of the form of ointment, cream, gel, liquid, poultice, and plaster. However, the type or form of agent of the local anesthetic for external use of the present invention is preferably a gel form agent. Those usable as the arbitrary components appropriately contained in conformity with the various types or forms of agents may be used within a range in which the effect of the present invention is not deteriorated.
For example, when the local anesthetic for external use of the present invention is the gel form agent which is preferred in the present invention, those usable as the arbitrary components include, for example, polyvalent alcohol and high molecular weight additives such as polyvinyl alcohol and cellulose derivatives. Those usable as polyvinyl alcohol preferably include those having a molecular weight of about 1700 to 2400. Those usable as the cellulose derivative include, for example, sodium carboxymethyl cellulose, hydroxypropyl cellulose, and hydroxypropylmethyl cellulose. Specifically, those usable as the polyvalent alcohol may include, for example, glycerol, propylene glycol, 1,3-butanediol, and polyethylene glycol.
A coloring agent such as a tar dye can be added to the local anesthetic for external use of the present invention, regardless of the type or form of agent, if necessary. Accordingly, it is possible to obtain a colored pharmaceutical preparation. Specifically, those usable as the coloring agent include coloring materials prescribed by the Pharmaceutical Affairs Law. Such coloring materials include, as the tar dye, for example, Amaranth, New Coccine, Phloxine B. and Rose Bengale.
The method for producing the local anesthetic for external use of the present invention may include ordinary production methods to be used corresponding to the various types or forms of agents to which the local anesthetic for external use of the present invention is applied. Specifically, for example, when the local anesthetic for external use of the present invention is produced as the gel form agent which is a preferred type or form of agent for the local anesthetic for external use of the present invention, the following method can be exemplified. However, the present invention is not limited to the following method for producing the local anesthetic for external use.
At first, the percutaneous absorption accelerator and the active ingredient selected from lidocaine, prilocaine, and pharmaceutically acceptable salts thereof are dissolved in a mixed solution comprising ethanol and/or isopropyl alcohol and water. Alternatively, the active ingredient and the percutaneous absorption accelerator are separately dissolved in ethanol and/or isopropyl alcohol, or water, or a mixed solution thereof respectively, and obtained respective solutions are mixed with each other. After that, a solution obtained by dissolving a gelling agent such as a high molecular weight additive or polyvalent alcohol in ethanol and/or isopropyl alcohol, water, or a mixed solution thereof is mixed with the foregoing solution containing the active ingredient and the percutaneous absorption accelerator to obtain a gel form agent. During this process, it is also possible to add beforehand a part of the active ingredient and/or a part of the percutaneous absorption accelerator to the solution of the gelling agent, if necessary. During the foregoing dissolving process and/or the mixing process, it is allowable to perform, for example, heating and agitation. Further, during the dissolving process and/or the mixing process performed in the production method described above, it is possible to add the arbitrary components such as the pH-adjusting agent, the coloring agent, polyvalent alcohol, and perfumes, if necessary.
The local anesthetic for external use of the present invention obtained as described above is less stimulus to skin, and it can be applied to a broad skin surface, while having a sufficient adsorptive force to skin. Accordingly, the local anesthetic for external use of the present invention is excellent and convenient for use such that, for example, it can be easily applied, while it can be conveniently peeled off. The local anesthetic for external use of the present invention forms a coating when it is used. Therefore, the active ingredient is percutaneously absorbed well, and it is possible to express the anesthetic effect within a short period of time. Further, the local anesthetic for external use of the present invention is excellent in stability when it is formulated to be a pharmaceutical preparation.